Project Description The fungal pathogen Candida albicans is the most common cause of invasive fungal infection often originating from outgrowth and invasion from the GI tract. Invasion initially causes intra- abdominal infections (IAI), which are often polymicrobial, and can lead to bloodstream infection and fatal sepsis. When fungal species are involved, mortality rates increase dramatically to 50- 75% depending on patient risk factors. We recently developed an animal model of polymicrobial fungal/bacterial intra-abdominal infection (IAI) with C. albicans (Ca) and Staphylococcus aureus (Sa) that mimics clinical invasive disease (dissemination/sepsis) resulting in 80-100% mortality within 96 h post-inoculation. In contrast, co-infection with the closely related C. dubliniensis (Cd) resulted in <10% mortality. Of particular interest, survivors of Cd/Sa or Cd alone re-challenged with a lethal co-infection (Ca/Sa) resulted in >90% survival. The protective response is sustained long term (up to at least 60 days prior to re-challenge) and is broad-spectrum providing protection against similarly lethal C. tropicalis/Sa and C. krusei/Sa IAI. Surprisingly, the Cd-induced protection against lethal IAI is NOT mediated by adaptive immunity, but instead appears to be through a mechanism of trained innate immunity (non-specific memory mediated by innate cells). Preliminary data indicate that the trained innate response by Cd is mediated by Gr-1+ myeloid derived suppressor cells (MDSC) that have been reported in human sepsis. The concept of trained innate immunity mediated by MDSCs is novel for infectious disease. Accordingly, our central hypothesis is that exposure to low virulence Candida species induce sustained broad spectrum trained innate immune protection against lethal polymicrobial fungal-bacterial sepsis. Mechanistically, we hypothesize that the protective response is mediated by epigenetically re- programed MDSCs during trained innate immunity. The objective of this proposal is to define host and microbial requirements for induction of protective trained innate immunity during polymicrobial sepsis and investigate mechanisms involved in induction, training and effector functions.